Implantable medical devices are used in the treatment and assessment of a variety of medical conditions. Such devices may be introduced into the body for a short period of time or may be placed therein permanently and have been used for the treatment of diseased, injured, or deformed body vessels. In cases where malfunctioning body vessels have reduced inner diameters, there is usually reduced flow of vital fluid or gas through the vessels and in extreme cases, the vessels often are occluded. Implantable medical devices have proven useful to open and/or expand, or to otherwise treat such obstructed or constricted vessels. These devices often are placed inside the vessel for a period of time and serve to mechanically support the inside of the malfunctioning vessel to keep the vessel open or patent.
The coated implantable medical device may be partly or completely placed into the esophagus, trachea, colon, biliary tract, urinary tract, vascular system or other location within a human or veterinary patient. Many treatments of the vascular or other systems involve the insertion of a stent, a catheter, a balloon, a wire guide, a cannula or the like into such a location within a human or veterinary patient. A stent is most simply considered as a cylinder of relatively short length which opens a body passage or lumen or which maintains a body passage or lumen in an open condition. In addition, balloons such as angioplasty or dilation balloons are expanded to open a body passage or vessel lumen, thereby causing potential trauma or injury to the expanded passage or vessel.
While implantable medical devices have gained widespread use, they do have attendant drawback. For example, introduction of a stent into the vascular system of a patient may cause the blood vessel walls into which the stent is being placed to become disrupted or injured. Healing of the injury site will involve clot formation (i.e., thrombosis), thereby causing stenosis (i.e., vessel closing) of the blood vessel. Moreover, if the medical device is left within the patient for an extended period of time, thrombus often forms on the device itself, again causing stenosis. As a result, the patient is placed at risk of a variety of complications, including heart attack, pulmonary embolism, and stroke. Thus, the use of such a medical device can entail the risk of precisely the problems that its use was intended to ameliorate.
Another site of injury during implantation of medical devices is the tissue at and beyond the ends of the implanted stent. Regardless of the cause of the trauma or injury to the vessel wall, the tissue will react such as with smooth muscle cell proliferation and the like thereby creating an adverse reaction and subsequent closure or stenosis of the vessel.
Another way in which blood vessels undergo stenosis is through disease. Probably the most common disease causing stenosis of blood vessels is atherosclerosis. Indeed, atherosclerotic vascular disease, in the form of coronary artery and peripheral vascular disease remains the leading cause of mortality in the United States. [1] Many medical devices and therapeutic methods are known for the treatment of atherosclerotic disease. Autogenous veins are the first choice of treatment for vein grafts because of their long-term patency especially in below knee anastomosis. However, for many patients suitable vein grafts are not available. [2] Allografts are in short supply and carry the risk of poor healing characterized by slow wall lysis, compaction and loss of elastic tissue, ulceration, mural thrombosis, and calcification. [3] Large-diameter (>6 mm inner diameter) blood vessels could be replaced by using non-degradable polymeric materials such as Dacron (polyethylene terephthalate) and ePTFE (expanded polytetrafluorotethylene).
Unfortunately, Dacron and ePTFE are not applicable to small-diameter (≦6 mm inner diameter) blood vessels (SDBV), especially in locations below the knee. Synthetic materials trigger inflammatory responses and activate platelets and leukocytes, initiating thrombogenesis and intimal hyperplasia. Poor patency is problematic due in part to incomplete endothelialization, thrombosis, and intimal hyperplasia particularly at the distal anastomosis. [10, 11]
Tissue engineering is an emerging alternative which utilizes biodegradable scaffolds seeded with cells to reconstruct lost tissues or organs. Significant progress has been made for in vitro regeneration of SDBV, [4-6] however, there is still a long way to go before tissue engineered blood vessel substitutes are approved by Food and Drug Adminstration (FDA). [7] Modification of existing vascular grafts to improve performance remains a viable option with room for innovation. It is well known that synthetic grafts do not spontaneously endothelialize in humans. In addition, the highly hydrophobic surfaces of ePTFE grafts limit endothelial cell adhesion. Various modifications have been proposed to either stimulate in vivo graft endothelialization or improve the retention of in vitro seeded endothelial cells when they are exposed to physiological blood flow. [12]. These modifications included coating or immobilization of endothelial-specific adhesion ligands such as collagen, albumin, thrombomodulin, gelatin, fibronectin, collagen-elastin matrices, dipyridamole, fibrin glue, heparin, and peptides (such as RGD, REDV). [13-17] However, issues of stability of the coating, transmission of pathogens, and high costs remain. [18] Plasma treatment is a convenient and widely used method for modifying the surface of materials without altering their bulk properties, [19-23] typically used to confer hydrophilicity to a surface. However, without the inclusion of a polymerizable agent, the plasma-induced effects are temporary and difficult to control. Using plasma to polymerize compounds such as ethylene to form a coating on materials can provide a modified surface that is stable. [24] Nevertheless, the resulting film is normally non-degradable, and long-term biocompatibility and the increased compliance mismatch of the modified grafts are a concern.
It would be desirable to develop implantable medical devices and methods for reliably delivering suitable therapeutic and diagnostic agents, drugs and other bioactive materials directly into a body portion during or following a medical procedure, so as to treat or prevent the abrupt closure and/or restenosis of a body portion such as a passage, lumen or blood vessel.